Carboxylic acid derivatives, their preparation and use

ABSTRACT

Carboxylic acid derivatives                    
     where R—R 6 , X, Y and Z have the meanings stated in the description, and the preparation thereof, are described. The novel compounds are suitable for controlling diseases.

This is a Divisional Application of application Ser. No. 09/184,152,filed on Nov. 02, 1998, which is a Divisional Application of applicationSer. No. 08/809,699, filed on Mar. 27, 1997, which is a National StageApplication under 35 U.S.C. 371, based on International Application No.PCT/EP 95/03,963, filed Oct. 07, 1995.

The present invention relates to novel carboxylic acid derivatives,their preparation and use.

Endothelin is a peptide which is composed of 21 amino acids and issynthesized and released by the vascular endothelium. Endothelin existsin three isoforms, ET-1, ET-2 and ET-3. In the following text,“endothelin” or “ET” signifies one or all isoforms of endothelin.Endothelin is a potent vasoconstrictor and has a potent effect on vesseltone. It is known that this vasoconstriction is caused by binding ofendothelin to its receptor (Nature, 332, (1988) 411-415; FEBS Letters,231, (1988) 440-444 and Biochem. Biophys. Res. Commun., 154, (1988)868-875).

Increased or abnormal release of endothelin causes persistentvasoconstruction in the peripheral, renal and cerebral blood vessels,which may lead to illnesses. It has been reported in the literature thatelevated plasma levels of endothelin were found in patients withhypertension, acute myocardial infarct, pulmonary hypertension,Raynaud's syndrome, atherosclerosis and in the airways of asthmatics(Japan J. Hypertension, 12, (1989) 79, J. Vascular Med. Biology 2,(1990) 207, J. Am. Med. Association 264, (1990) 2868).

Accordingly, substances which specifically inhibit the binding ofendothelin to the receptor ought also to antagonize the variousabovementioned physiological effects of endothelin and therefore bevaluable drugs.

We have found that certain carboxylic acid derivatives are goodinhibitors of endothelin receptors.

The invention relates to carboxylic acid derivatives of the formula I

where R is formyl, tetrazole, nitrile, a COOH group or a radical whichcan be hydrolyzed to COOH, and the other substituents have the followingmeanings:

R² hydrogen, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂, halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio;

X nitrogen or CR¹⁴ where R¹⁴ is hydrogen or C₁₋₅-alkyl, or CR¹⁴ formstogether with CR³ a 5- or 6-membered alkylene or alkenylene ring whichcan be substituted by one or two C₁₋₄-alkyl groups and in which in eachcase a methylene group can be replaced by oxygen, sulfur, —NH or—NC₁₋₄-alkyl;

R³ hydrogen, hydroxyl, NH₂, NH(C₁-C₄-Alkyl), N(C₁-C₄-alkyl)₂, halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,—NH—O—C₁₋₄-alkyl, C₁-C₄-alkylthio or CR³ is linked to CR¹⁴ as indicatedabove to give a 5- or 6-membered ring;

R⁴ and R⁵ (which can be identical or different):

phenyl or naphthyl, which can be substituted by one or more of thefollowing radicals: halogen, nitro, cyano, hydroxyl, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino or C₁-C₄-dialkylamino; or

phenyl or naphthyl, which are connected together in the ortho positionsvia a direct linkage, a methylene, ethylene or ethenylene group, anoxygen or sulfur atom or an SO₂-, NH- or N-alkyl group, orC₃-C₇-cycloalkyl;

R⁶ hydrogen, C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl orC₃-C₈-cycloalkyl, where each of these radicals can be substituted one ormore times by: halogen, nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy,C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₃-₈-alkylcarbonylalkyl,C₁-C₄-alkylamino, di-C₁-C₄-alkylamino, phenyl or phenyl or phenoxy whichis substituted one or more times, eg. one to three times, by halogen,nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;

phenyl or naphthyl, each of which can be substituted by one or more ofthe following radicals: halogen, nitro, cyano, hydroxyl, amino,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, C₁-C₄-alkylamino, C₁-C₄-dialkylamino, dioxomethylene ordioxoethylene;

a five- or six-membered heteroaromatic moiety containing one to threenitrogen atoms and/or one sulfur or oxygen atom, which can carry one tofour halogen atoms and/or one or two of the following radicals:C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possiblefor the phenyl radicals in turn to carry one to five halogen atomsand/or one to three of the following radicals: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio;

with the proviso that R⁶ can be hydrogen only when Z is not a singlebond;

Y sulfur or oxygen or a single bond;

Z sulfur or oxygen or a single bond.

The compounds, and the intermediates for preparing them, such as IV andVI, may have one or more asymmetrical substituted carbon atoms. Suchcompounds may be in the form of the pure enantiomers or purediastereomers or a mixture thereof. The use of an enantiomerically purecompound as active substance is preferred.

The invention furthermore relates to the use of the abovementionedcarboxylic acid derivatives for producing drugs, in particular forproducing endothelin receptor inhibitors.

The invention furthermore relates to the preparation of the compounds ofthe formula IV in enantiomerically pure form. Enantioselectiveepoxidation of an olefin with two phenyl substituents is known (J. Org.Chem. 52, 1994, 4378-4380). We have now found, surprisingly, that evenester groups in these systems permit epoxidation in high optical purity.

The preparation of the compounds according to the invention where Z issulfur or oxygen starts from the epoxides IV, which are obtained in aconventional manner, eg. as described in J. March, Advanced OrganicChemistry, 2nd ed., 1983, page 862 and page 750, from the ketones II orthe olefins III:

Carboxylic acid derivatives of the general formula VI can be prepared byreacting the epoxides of the general formula IV (eg. with R=ROOR¹⁰ withalcohols or thiols of the general formula V where R⁶ and Z have themeanings stated in claim 1.

To do this, compounds of the general formula IV are heated withcompounds of the formula V, in the molar ratio of about 1:1 to 1:7,preferably 1 to 3 mole equivalents, to 50-200° C., preferably 80-150° C.

The reaction can also take place in the presence of a diluent. Allsolvents which are inert toward the reagents used can be used for thispurpose.

Examples of such solvents or diluents are water, aliphatic, alicyclicand aromatic hydrocarbons, which may in each case be chlorinated, suchas hexane, cyclohexane, petroleum ether, naphtha, benzene, toluene,xylene, methylene chloride, chloroform, carbon tetrachloride, ethylchloride and trichloroethylene, ethers such as diisopropyl ether,dibutyl ether, methyl tert-butyl ether, propylene oxide, dioxane andtetrahydrofuran, ketones such as acetone, methyl ethyl ketone, methylisopropyl ketone and methyl isobutyl ketone, nitrites such asacetonitrile and propionitrile, alcohols, such as methanol, ethanol,isopropanol, butanol and ethylene glycol, esters such as ethyl acetateand amyl acetate, amides such as dimethylformamide, dimethylacetamideand N-methylpyrrolidone, sulfoxides and sulfones, such as dimethylsulfoxide and sulfolane, bases such as pyridine, cyclic ureas such as1,3-dimethylimidazolidin-2-one and1,3-dimethyl-3,4,5,6-tetra-hydro-2(1H)-pyrimidinone.

The reaction is preferably carried out at a temperature in the rangefrom 0° C. to the boiling point of the solvent or mixture of solvents.

The presence of a catalyst may be advantageous. Suitable catalysts arestrong organic and inorganic acids, and Lewis acids. Examples thereofare, inter alia, sulfuric acid, hydrochloric acid, trifluoroacetic acid,p-toluenesulfonic acid, boron trifluoride etherate and titanium(IV)alcoholates.

Compounds of the formula VI where R⁴ and R⁵ are cycloalkyl can also beprepared by subjecting compounds of the formula VI where R⁴ and R⁵ arephenyl, naphthyl, or phenyl or naphthyl substituted as described above,to a nuclear hydrogenation.

Compounds of the formula VI can be obtained in enantiomerically pureform by starting from enantiomerically pure compounds of the formula IVand reacting them in the manner described with compounds of the formulaV.

It is furthermore possible to obtain enantiomerically pure compounds ofthe formula VI by carrying out a classical racemate resolution onracemic or diastereomeric compounds of the formula VI using suitableenantiomerically pure bases such as brucine, strychnine, quinine,quinidine, chinchonidine [sic], chinchonine [sic], yohimbine, morphine,dehydroabietylamine, ephedrine (−), (+), deoxyephedrine (+), (−),threo-2-amino-1-(p-nitrophenyl)-1,3-propanediol (+), (−),threo-2-(N,N-dimethylamino)-1-(p-nitrophenyl)-1,3-propanediol (+), (−)threo-2-amino-1-phenyl-1,3-propanediol (+), (−), α-methylbenzylamine(+), (−), α-(1-naphthyl)ethylamine (+), (−), α-(2-naphthyl)ethylamine(+), (−), aminomethylpinane, N,N-dimethyl-1-phenylethylamine,N-methyl-1-phenylethylamine, 4-nitrophenylethylamine, pseudoephedrine,norephedrine, norpseudoephedrine, amino acid derivatives, peptidederivatives.

The compounds according to the invention where Y is oxygen, and theremaining substituents have the meanings stated under the generalformula I, can be prepared, for example, by reacting the carboxylic acidderivatives of the general formula VI where the substituents have thestated meanings with compounds of the general formula VII

where R¹⁵ is halogen or R¹⁶—SO₂—, where R¹⁶ can be C₁-C₄-alkyl,C₁-C₄-haloalkyl or phenyl. The reaction preferably takes place in one ofthe abovementioned inert diluents with the addition of a suitable base,ie. of a base which deprotonates the intermediate VI, in a temperaturerange from room temperature to the boiling point of the solvent.

Compounds of the formula VII are known, some of them can be bought, orthey can be prepared in a generally known manner.

It is possible to use as base an alkali metal or alkaline earth metalhydride such as sodium hydride, potassium hydride or calcium hydride, acarbonate such as an alkali metal carbonate, eg. sodium or potassiumcarbonate, an alkali metal or alkaline earth metal hydroxide such assodium or potassium hydroxide, an organometallic compound such asbutyllithium, or an alkali metal amide such as lithium diisopropylamide.

The compounds according to the invention where Y is sulfur, and theremaining substituents have the meanings stated under the generalformula I, can be prepared, for example, by reacting carboxylic acidderivatives of the general formula VIII, which can be obtained in aknown manner from compounds of the general formula VI and in which thesubstituents have the abovementioned meanings, with compounds of thegeneral formula IX, where R², R³ and X have the meanings stated undergeneral formula I.

The reaction preferably takes place in one of the abovementioned inertdiluents with the addition of a suitable base, ie. a base whichdeprotonates the intermediate IX, in a temperature range from roomtemperature to the boiling point of the solvent.

It is possible to use as base, besides those mentioned above, organicbases such as triethylamine, pyridine, imidazole ordiazabicycloundecane.

Carboxylic acid derivatives of the formula VIa (Z in formula VI=directlinkage) can be prepared by reacting epoxides of the formula IV withcuprates of the formula XI:

The cuprates can be prepared as described in Tetrahedron Letters 23,(1982) 3755.

Compounds of the formula I can also be prepared by starting from thecorresponding carboxylic acids, ie. compounds of the formula I where Ris COOH, and initially converting these in a conventional manner into anactivated form, such as a halide, an anhydride or imidazolide, and thenreacting the latter with an appropriate hydroxy compound HOR¹⁰. Thisreaction can be carried out in the usual solvents and often requiresaddition of a base, in which case those mentioned above are suitable.These two steps can also be simplified, for example, by allowing thecarboxylic acid to act on the hydroxy compound in the presence of adehydrating agent such as a carbodiimide.

In addition, it is also possible for compounds of the formula I to beprepared by starting from the salts of the corresponding carboxylicacids, ie. from compounds of the formula I where R is COR¹ and R¹ is OM,where M can be an alkali metal cation or the equivalent of an alkalineearth metal cation. These salts can be reacted with many compounds ofthe formula R¹—A where A is a conventional nucleofugic leaving group,for example halogen such as chlorine, bromine, iodine or aryl- oralkylsulfonyl which is unsubstituted or substituted by halogen, alkyl orhaloalkyl, such as toluenesulfonyl and methylsulfonyl, or anotherequivalent leaving group. Compounds of the formula R¹—A with a reactivesubstituent A are known or can be easily obtained with general expertknowledge. This reaction can be carried out in conventional solvents andadvantageously takes place with the addition of a base, in which casethose mentioned above are suitable.

The radical R in formula I may vary widely. For example, R is a group

where R¹ has the following meanings:

a) hydrogen;

b) succinylimidoxy;

c) a five-membered heteroaromatic moiety linked by a nitrogen atom, suchas pyrrolyl, pyrazolyl, imidazolyl and triazolyl, which may carry one ortwo halogen atoms, in particular fluorine and chlorine and/or one or twoof the following radicals:

C₁-C₄-alkyl such as methyl, ethyl, 1-propyl, 2-propyl,2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl;

C₁-C₄-haloalkyl, in particular C₁-C₂-haloalkyl such as fluoromethyl,difluoromethyl, trifluoromethyl, chlorodifluoromethyl,dichlorofluoromethyl, trichloromethyl, 1-fluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl;

C₁-C₄-haloalkoxy, in particular C₁-C₂-haloalkoxy such asdifluoromethoxy, trifluoromethoxy, chlorbdifluoromethoxy,1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy,2-chloro-1,1,2-trifluoroethoxy and pentafluoroethoxy, in particulartrifluoromethoxy;

C₁-C₄-alkoxy such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy,1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy, in particularmethoxy, ethoxy, 1-methylethoxy;

C₁-C₄-alkylthio such as methylthio, ethylthio, propylthio,1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio,1,1-dimethylethylthio, in particular methylthio and ethylthio;

d) R¹ furthermore a radical

where m is 0 or 1 and R⁷ and R⁸, which can be identical or different,have the following meanings:

hydrogen

C₁-C₈-alkyl, in particular C₁-C₄-alkyl as mentioned above;

C₃-C₆-alkenyl such as 2-propenyl, 2-butenyl, 3-butenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl; 1-ethyl-2-propenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl,2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl,1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl,1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, inparticular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl and3-methyl-2-pentenyl;

C₃-C₆-alkynyl such as 2-propynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl,1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl,1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl,2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably2-propynyl, 2-butynyl, 1-methyl-2-propynyl and 1-methyl-2-butynyl, inparticular 2-propynyl

C₃-C₈-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, cyclooctyl, where these alkyl, cycloalkyl,alkenyl and alkynyl groups can each carry one to five halogen atoms, inparticular fluorine or chlorine and/or one or two of the followinggroups:

C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy asmentioned above, C₃-C₆-alkenyloxy, C₃-C₆-alkenylthio, C₃-C₆-alkynyloxy,C₃-C₆-alkynylthio, where the alkenyl and alkynyl constituents present inthese radicals preferably have the abovementioned meanings;

C₁-C₄-alkylcarbonyl such as, in particular, methylcarbonyl,ethylcarbonyl, propylcarbonyl, 1-methylethylcarbonyl, butylcarbonyl,1-methylpropylcarbonyl, 2-methylpropylcarbonyl,1,1-dimethylethylcarbonyl;

C₁-C₄-alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, 1-methylethoxycarbonyl, butyloxycarbonyl,1-methylpropyloxycarbonyl, 2-methylpropyloxycarbonyl,1,1-dimethylethoxycarbonyl;

C₃-C₆-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl, C₃-C₆-alkenyloxycarbonyland C₃-C₆-alkynyloxycarbonyl, where the alkenyl and alkynyl radicals arepreferably defined as detailed above;

phenyl, unsubstituted or substituted one or more times, eg. one to threetimes, by halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio, such as2-fluorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-methylphenyl,3-nitrophenyl, 4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl,4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl,2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl, 2-nitro-5-cyanophenyl,2,6-difluorophenyl;

di-C₁-C₄-alkylamino such as, in particular, dimethylamino,dipropylamino, N-propyl-methylamino, N-propyl-ethylamino,diisopropylamino, N-isopropyl-methylamino, N-isopropyl-N-ethylamino,N-isopropyl-propylamino;

R⁷ and R⁸ furthermore phenyl which can be substituted by one or more,eg. one to three, of the following radicals: halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio, as mentioned above in particular;

or R⁷ and R⁸ together form a C₄-C₇-alkylene chain which is closed toform a ring, is unsubstituted or substituted, eg. substituted byC₁-C₄-alkyl, and may contain a heteroatom selected from the groupconsisting of oxygen, sulfur or nitrogen, such as —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₆—, —(CH₂)₇—, —(CH₂)₂—O—(CH₂)₂—, —CH₂—S—(CH₂)₃—,—(CH₂)₂—O—(CH₂)₃—, —NH—(CH₂ )₃—, —CH₂—NH—(CH₂)₂—, —CH₂—CH═CH=CH₂—,—CH═CH—(CH₂ )₃—;

e) R¹ furthermore a group

where k is 0, 1 and 2, p is 1, 2, 3 and 4 and R⁹ is

C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl orunsubstituted or substituted phenyl, as mentioned above in particular.

f) R¹ furthermore a radical OR¹⁰, where R¹⁰ is:

hydrogen, the cation of an alkali metal such as lithium, sodium,potassium or the cation of an alkaline earth metal such as calcium,magnesium and barium or an environmentally compatible organic ammoniumion such as tertiary C₁-C₄-alkylammonium or the ammonium ion;

C₃-C₈-cycloalkyl as mentioned above, which may carry one to threeC₁-C₄-alkyl groups;

C₁-C₈-alkyl such as, in particular, methyl, ethyl, propyl,1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl,pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,2-dimethylpropyl,1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl,2-ethylbutyl, 1-ethyl-2-methylpropyl, which can carry one to fivehalogen atoms, in particular fluorine and chlorine and/or one of thefollowing radicals:

C₁-C₄-alkoxy, C₁-C₄-alkylthio, cyano, C₁-C₄-alkylcarbonyl,C₃-C₈-cycloalkyl, C₁-C₄-alkoxycarbonyl, phenyl, phenoxy orphenylcarbonyl, where the aromatic radicals in turn can carry in eachcase one to five halogen atoms and/or one to three of the followingradicals: nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio, as mentioned above inparticular;

a C₁-C₈-alkyl as mentioned above, which can carry one to five halogenatoms, in particular fluorine and/or chlorine, and carries one of thefollowing radicals: a 5-membered heteroaromatic moiety containing one tothree nitrogen atoms, or a 5-membered heteroaromatic moiety containing anitrogen atom and an oxygen or sulfur atom, which can carry one to fourhalogen atoms and/or one or two of the following radicals:

nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl,C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio. Particular mention may be madeof: 1-pyrazolyl, 3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl,3,5-dimethyl-1-pyrazolyl, 3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl,4-chloro-1-pyrazolyl, 4-bromo-1-pyrazolyl, 1-imidazolyl,1-benzimidazolyl, 1,2,4-triazol-1-yl, 3-methyl-1,2,4-triazol-1-yl,5-methyl-1,2,4-triazol-1-yl, 1-benzotriazolyl, 3-isopropyl-5-isoxazolyl,3-methyl-5-isoxazolyl, 2-oxazolyl, 2-thiazolyl, 2-imidazolyl,3-ethyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl, 3-tert-butyl-5-isoxazolyl;

a C₂-C₆-alkyl group which carries one of the following radicals inposition 2: C₁-C₄-alkoxyimino, C₃-C₆-alkynyloxyimino,C₃-C₆-haloalkenyloxyimino or benzyloxyimino;

a C₃-C₆-alkenyl or C₃-C₆-alkynyl group, it being possible for thesegroups in turn to carry one to five halogen atoms;

R¹⁰ furthermore a phenyl radical which can carry one to five halogenatoms and/or one to three of the following radicals: nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,

C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio, as mentioned above inparticular;

a 5-membered heteroaromatic moiety which is linked via a nitrogen atom,contains one to three nitrogen atoms and can carry one or two halogenatoms and/or one or two of the following radicals: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/orC₁-C₄-alkylthio. Particular mention may be made of: 1-pyrazolyl,3-methyl-1-pyrazolyl, 4-methyl-1-pyrazolyl, 3,5-dimethyl-1-pyrazolyl,3-phenyl-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 4-chloro-1-pyrazolyl,4-bromo-1-pyrazolyl, 1-imidazolyl, 1-benzimidazolyl, 1,2,4-triazol-1-yl,3-methyl-1,2,4-triazol-1-yl, 5-methyl-1,2,4-triazol-1-yl),1-benzotriazolyl, 3,4-dichloro-1-imidazolyl;

R¹⁰ furthermore a group

where R¹¹ and R¹², which can be identical or different, are:

C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, it beingpossible for these radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthioand/or an unsubstituted or substituted phenyl radical, as mentionedabove in particular;

phenyl which can be substituted by one or more, eg. one to three, of thefollowing radicals: halogen, nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio, where these radicalsare, in particular, those mentioned above;

or R¹¹ and R¹² together form a C₃-C₁₂-alkylene chain which can carry oneto three C₁-C₄-alkyl groups and contain a heteroatom from the groupconsisting of oxygen, sulfur and nitrogen, as mentioned in particularfor R⁷ and R⁸.

g) R¹ furthermore a radical

where R¹³ is:

C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₆-cycloalkyl as mentionedabove in particular, it being possible for these radicals to carry aC₁-C₄-alkoxy, C₁-C₄-alkylthio and/or a phenyl radical as mentionedabove;

phenyl, unsubstituted or substituted, in particular as mentioned above.

h) R¹ a radical

where R¹³ has the abovementioned meaning.

R can furthermore be:

tetrazole or nitrile.

In respect of the biological effect, preferred carboxylic acidderivatives of the general formula I, both as pure enantiomers and purediastereomers or as mixture thereof, are those where the substituentshave the following meanings:

R² hydrogen, hydroxyl, N(C₁-C₄-alkyl)₂, the C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio groupsand halogen atoms mentioned in detail for R¹, especially chlorine,methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy;

X nitrogen or CR¹⁴ where

R¹⁴ is hydrogen or alkyl, or CR¹⁴ forms together with CR³ a 4- to5-membered alkylene or alkenylene ring in which, in each case, amethylene group can be replaced by oxygen or sulfur, such as—CH₂—CH₂—O—, —CH═CH—O—, —CH₂—CH₂—CH₂—O—, —CH═CH—CH₂O—, in particularhydrogen, —CH₂—CH₂O—, —CH(CH₃)—CH(CH₃)—O—, —C(CH₃)═C(CH₃)—O—,—CH═C(CH₃)—O— or —C(CH₃)═C(CH₃)—S;

R³ the hydrogen, hydroxyl, N(C₁-C₄-alkyl)₂, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylthio groupsand halogen atoms mentioned for R¹, especially chlorine, methyl,methoxy, ethoxy, difluoromethoxy, trifluoromethoxy or is linked to R¹⁴as mentioned above to give a 5- or 6-membered ring;

R⁴ and R⁵ phenyl or naphthyl, which can be substituted by one or more,eg. one to three, of the following radicals: halogen, nitro, cyano,hydroxyl, mercapto, amino, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, C₁-C₄-alkylamino,di-C₁-C₄-alkylamino, C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl; phenylor naphthyl, which are connected together in the ortho positions by adirect linkage, a methylene, ethylene or ethenylene group, an oxygen orsulfur atom or an SO₂, NH or N-alkyl group, or C₃-C₇-cycloalkyl;

R⁶ C₁-C₈-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or C₃-C₈-cycloalkyl asmentioned above in particular, it being possible for these radicals ineach case to be substituted one or more times by: halogen, hydroxyl,nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy,C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₁-C₄-alkylcarbonyl, hydroxycarbonyl,C₁-C₄-alkoxycarbonyl, C₁-C₄-alkylamino, di-C₁-C₄-alkylamino orunsubstituted or substituted phenyl or phenoxy, as mentioned above inparticular;

phenyl or naphthyl, which can be substituted by one or more of thefollowing radicals: halogen, nitro, cyano, hydroxyl, amino, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, C₂-C₄-alkylamino or C₁-C₄-dialkylamino, as mentioned inparticular for R⁷ and R⁴;

a five- or six-membered heteroaromatic moiety which contains one tothree nitrogen atoms and/or one sulfur or oxygen atom and which cancarry one to four halogen atoms and/or one or two of the followingradicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylthio, phenyl, phenoxy or phenylcarbonyl, it being possiblefor the phenyl radicals in turn to carry one to five halogen atomsand/or one to three of the following radicals: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio,as mentioned for R⁴ in particular;

Y sulfur, oxygen or a single bond;

Z sulfur, oxygen, —SO—, —SO₂— or a single bond.

Particularly preferred compounds of the formula I, both as pureenantiomers and pure diastereomers or as mixture thereof, are those inwhich the substituents have the following meanings:

R² C₁-C₄-alkyl, C₁-C₄-alkoxy

X nitrogen or CR¹⁴, where

R¹⁴ is hydrogen or alkyl, or CR¹⁴ forms together with CR³ a 4- or5-membered alkylene or alkenylene ring such as —CH₂—CH₂—CH₂—,—CH═CH—CH₂—, in which in each case a methylene group can be replaced byoxygen or sulfur, such as —CH₂—CH₂—O—, —CH═CH—O—, —CH₂—CH₂—CH₂—O—,—CH═CH—CH₂O—, in particular hydrogen, —CH₂—CH₂—O—, —CH(CH₃)—CH(CH₃)—O—,—C(CH₃)═C(CH₃)—O—, —CH═C(CH₃)—O— or —C(CH₃)═C(CH₃)—S;

R³ the C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio groups mentioned forR¹, or is linked to R¹⁴ as mentioned above to give a 5- or 6-memberedring;

R⁴ and R⁵ phenyl (identical or different) which can be substituted byone or more, eg. one to three, of the following radicals: halogen,nitro, hydroxyl, C₁-C₄-alkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio or

R⁴ and R⁵ are phenyl groups which are connected together in the orthopositions by a direct linkage, a methylene, ethylene or ethenylenegroup, an oxygen or sulfur atom or an SO₂, NH or N-alkyl group; or

R⁴ and R⁵ are C₃-C₇-cycloalkyl;

R⁶ C₁-C₈-alkyl, C₃-C₆-alkenyl or C₃-C₈-cycloalkyl, it being possible forthese radicals in each case to be substituted one or more times by:halogen, hydroxyl, nitro, cyano, C₁-C₄-alkoxy, C₃-C₆-alkenyloxy,C₁-C₄-alkylthio; phenyl or naphthyl, which can be substituted by one ormore of the following radicals: halogen, nitro, cyano, hydroxyl, amino,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, C₁-C₄-alkylamino or C₁-C₄-dialkylamino;

a five- or six-membered heteroaromatic moiety which contains a nitrogenatom and/or a sulfur or oxygen atom and which can carry one to fourhalogen atoms and/or one or two of the following radicals: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkylthio, phenyl, phenoxy orphenylcarbonyl, it being possible for the phenyl radicals in turn tocarry one to five halogen atoms and/or one to three of the followingradicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and/orC₁-C₄-alkylthio;

Y sulfur, oxygen or a single bond;

Z sulfur, oxygen, —SO—, —SO₂— or a single bond.

The compounds of the present invention provide a novel therapeuticpotential for the treatment of hypertension, pulmonary hypertension,myocardial infarct, angina pectoris, acute kidney failure, renalinsufficiency, cerebral vasospasms, cerebral ischemia, subarachnoidhemorrhages, migraine, asthma, atherosclerosis, endotoxic shock,endotoxin-induced organ failure, intravascular coagulation, restenosisafter angioplasty, benign prostate hyperplasia, or hypertension orkidney failure caused by ischemia or intoxication.

The good effect of the compounds can be shown in the following tests:

Receptor binding studies

Cloned human ET_(A) receptor-expressing CHO cells and guinea pigcerebellar membranes with >60% ET_(B) compared with ET_(A) receptorswere used for binding studies.

The ET_(A) receptor-expressing CHO cells were grown in F₁₂ mediumcontaining 10% fetal calf serum, 1% glutamine, 100 U/ml penicillin and0.2% streptomycin (Gibco BRL, Gaithersburg, Md., USA). After 48 h, thecells were washed with PBS and incubated with 0.05% trypsin-containingPBS for 5 min. Neutralization was then carried out with F₁₂ medium, andthe cells were collected by centrifugation at 300× g. To lyze the cells,the pellet was briefly washed with lysis buffer (5 mM Tris-HCl, pH 7.4with 10% glycerol) and then incubated at a concentration of 10⁷ cells/mlof lysis buffer at 4° C. for 30 min. The membranes were centrifuged at20,000× g for 10 min, and the pellet was stored in liquid nitrogen.

Guinea pig cerebella were homogenized in a Potter-Elvejhem homogenizerand obtained by differential centrifugation at 1000× g for 10 min andrepeated centrifugation of the supernatant at 20,000× g for 10 min.

Binding assays

For the ET_(A) and ET_(B) receptor binding assay, the membranes weresuspended in incubation buffer (50 mM Tris-HCl, pH 7.4 with 5 mM MnCl₂,40 μg/ml bacitracin and 0.2% BSA) at a concentration of 50 μg of proteinper assay mixture and incubated with 25 pM [125I]-ET₁ (ET_(A) receptorassay) or 25 pM [125I]-RZ₃ (ET_(B) receptor assay) in the presence andabsence of test substance at 25° C. The nonspecific binding wasdetermined using 10⁻⁷ M ET₁. After 30 min, the free and boundradioligand were separated by filtration through GF/B glass fiberfilters (Whatman, England) on a Skatron cell collector (Skatron, Lier,Norway) and the filters were washed with ice-cold Tris-HCl buffer, pH7.4 with 0.2% BSA. The radioactivity collected on the filters wasquantified using a Packard 2200 CA liquid scintillation counter.

Functional in vitro assay system to look for endothelin receptor(subtype A) antagonists

This assay system is a functional, cell-based assay for endothelinreceptors. When certain cells are stimulated with endothelin 1 (ET1)they show an increase in the intracellular calcium concentration. Thisincrease can be measured in intact cells loaded with calcium-sensitivedyes.

1-Fibroblasts which had been isolated from rats and in which anendogenous endothelin receptor of the A subtype had been detected wereloaded with the fluorescent dye Fura 2-an as follows: aftertrypsinization, the cells were resuspended in buffer A (120 mM 40 NaCl,5 mM KCl, 1.5 mM MgCl₂, 1 mM CaCl₂, 25 mM HEPES, 10 mM glucose, pH 7.4)to a density of 2×10⁶/ml and incubated with Fura 2-am (2 μM), PluronicsF-127 (0.04%) und DMSO (0.2%) at 37° C. in the dark for 30 min. Thecells were then washed twice with buffer A and resuspended at 2×10⁶/ml.

The fluorescence signal from 2×10⁵ cells per ml with Ex/Em 380/510 wasrecorded continuously at 30° C. The test substances and, after anincubation time of 3 min, ET1 to the cells, the maximum change in thefluorescence was determined. The response of the cells to ET1 withoutprevious addition of a test substance was used as control and was setequal to 100%.

Testing of ET antagonists in vivo

Male SD rats weighting 250-300 g were anesthetized with amobarbital,artificially ventilated, vagotomized and pithed. The carotid artery andjugular vein were cathetized.

In control animals, intravenous administration of 1 μg/kg ET1 led to adistinct rise in blood pressure which persisted for a lengthy period.

The test animals received an i.v. injection of the test compounds (1ml/kg) 5 min before the administration of ET1. To determine theET-antagonistic properties, the rise in blood pressure in the testanimals was compared with that in the control animals.

Endothelin-1-induced sudden death in mice

The principle of the test is the inhibition of the sudden heart deathcaused in mice by endothelin, which is probably induced by constrictionof the coronary vessels, by pretreatment with endothelin receptorantagonists. Intravenous injection of 10 nmol/kg endothelin in a volumeof 5 ml/kg of body weight results in death of the animals within a fewminutes.

The lethal endothelin-1 dose is checked in each case on a small group ofanimals. If the test substance is administered intravenously, theendothelin-1 injection which was lethal in the reference group usuallytakes place 5 min thereafter. With other modes of administration, thetimes before administration are extended, where appropriate up toseveral hours.

The survival rate is recorded, and effective doses which protect 50% ofthe animals (ED 50) from endothelin-induced heart death for 24 h orlonger are determined.

Functional test on vessels for endothelin receptor antagonists

Segments of rabbit aorta are, after an initial tension of 2 g and arelaxation time of 1 h in Krebs-Senseleit solution at 37° C. and pH7.3-7.4, first induced to contract with K⁺. After washing out, anendothelin dose-effect plot up to the maximum is constructed.

Potential endothelin antagonists are administered to other preparationsof the same vessel 15 min before starting the endothelin dose-effectplot. The effects of the endothelin are calibrated as a % of theK⁺-induced contraction. Effective endothelin antagonists result in ashift to the right in the endothelin dose-effect plot.

The compounds according to the invention can be administered orally orparenterally (subcutaneously, intravenously, intramuscularly,intraperotoneally) in a conventional way. Administration can also takeplace with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient andon the mode of administration. The daily dose of active substance is, asa rule, about 0.5-50 mg/kg of body weight on oral administration andabout 0.1-10 mg/kg of body weight on parenteral administration.

The novel compounds can be used in conventional solid or liquidpharmaceutical forms, eg. as uncoated or (film-)coated tablets,capsules, powders, granules, suppositories, solutions, ointments, creamsor sprays. These are produced in a conventional way. The activesubstances can for this purpose be processed with conventionalpharmaceutical aids such as tablet binders, fillers, preservatives,tablet disintegrants, flow regulators, plasticizers, wetting agents,dispersants, emulsifiers, solvents, release-slowing agents, antioxidantsand/or propellent gases (cf. H. Sucker et al.: PharmazeutischeTechnologie, Thieme-verlag, Stuttgart, 1991). The administration formsobtained in this way normally contain from 0.1 to 90% by weight of theactive substance.

SYNTHESIS EXAMPLES

Example 1

Methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate weredissolved in 50 ml of absolute methanol and, at 0° C., 0.1 ml of borontrifluoride etherate was added. The mixture was stirred at 0° C. for 2 hand at room temperature for a further 12 h. The solvent was distilledout, the residue was taken up in ethyl acetate, washed with sodiumbicarbonate solution and water and dried over magnesium sulfate. Afterremoval of the solvent by distillation there remained 5.5 g (88%) of apale yellow oil.

Example 2

Methyl 2-hydroxy-3-phenoxy-3,3-diphenylpropionate

5 g (19.6 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.6 g (60mmol) of phenol were heated together at 100° C. for 6 h. Removal of theexcess phenol by distillation under high vacuum and purification of theresidue by chromatography on silica gel with hexane/ethyl acetatemixtures resulted in 4.9 g (77%) of a pale yellow oil.

Example 3

Methyl2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate

2.86 g (10 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionatewere dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) ofsodium hydride was added. The mixture was stirred for 1 h and then 2.2 g(10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. Afterstirring at room temperature for 24 h, cautious hydrolysis was carriedout with 10 ml of water, the pH was adjusted to 5 with acetic acid, andthe solvent was removed by distillation under high vacuum. The residuewas taken up in 100 ml of ethyl acetate, washed with water and driedover magnesium sulfate, and the solvent was distilled out. The residuewas mixed with 10 ml of ether, and the resulting precipitate wasfiltered off with suction. After drying, 3.48 g (82%) of a white powderremained.

Melting point 81° C.

Example 4

2-(4,6-Dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid

2.12 g (5 mmol) of methyl2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionatewere dissolved in 50 ml of dioxane, 10 ml of 1 N KOH solution wereadded, and the mixture was stirred at 100° C. for 3 h. The solution wasdiluted with 300 ml of water and extracted with ethyl acetate to removeunreacted ester. The aqueous phase was then adjusted to pH 1-2 withdilute hydrochloric acid and extracted with ethyl acetate. After dryingover magnesium sulfate and removal of the solvent by distillation, theresidue was mixed with an ether/hexane mixture, and the precipitatewhich formed was filtered off with suction. After drying, 1.85 g (90%)of a white powder remained.

Melting point 167° C.

Example 5

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl sodiumpropionate

1.68 g (4 mmol) of2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionic acidare dissolved in 4 ml of 1N NaOH+100 ml of water. The solution isfreeze-dried, and the sodium salt of the carboxylic acid used isobtained quantitatively.

10 g (34.9 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionatewere dissolved in 50 ml each of methanol and glacial acetic acid, 1 mlof RuO(OH)₂ in dioxane was added, and hydrogenation was carried out withH₂ in an autoclave at 100° C. under 100 bar for 30 h. The catalyst wasfiltered off, the mixture was concentrated, mixed with ether and washedwith NaCl solution, and the organic phase was dried and concentrated.10,1 g of methyl 3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate wereobtained as an oil.

Example 7

Methyl2-[(4,6-dimethoxy-pyrimidin-2-yl)thio]-3-methoxy-3,3-diphenylpropionate

7.16 g (25 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionatewere dissolved in 50 ml of dichloromethane, 3 g (30 mmol) oftriethylamine were added, and 3.2 g (28 mmol) of methanesulfonylchloride were added dropwise while stirring. The mixture was stirred atroom temperature for 2 h, washed with water, dried over magnesiumsulfate and concentrated under reduced pressure. The residue was takenup in DMF and added dropwise at 0° C. to a suspension of 12.9 g (75mmol) of 4,6-dimethoxypyrimidine-2-thiol and 8.4 g (100 mmol) of sodiumbicarbonate in 100 ml of DMF. After stirring at room temperature for 2 hand at 60° C. for a further 2 h, the mixture was poured into 1 liter ofice-water, and the resulting precipitate was filtered off with suction.After drying, 3.19 g (29%) of a white powder remained.

Example 8

Methyl 2-hydroxy-3,3-diphenylbutyrate

1.5 g (5.9 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate dissolved in10 ml of absolute ether were added dropwise to a cuprate solution whichhad been prepared from 635 mg (7 mmol) of copper(I) cyanide dissolved in10 ml of absolute ether and 8.14 ml (13 mmol) of a 1.6 normalmethyllithium solution and had been cooled to −78° C. The solution wasstirred at −78° C. for 1 h and then allowed to warm to room temperature.It was subsequently diluted with 100 ml of ether and 100 ml of water,and the ether phase was washed with dilute citric acid and with sodiumbicarbonate solution and dried over magnesium sulfate. The crude productwas purified by chromatography on silica gel with cyclohexane/ethylacetate mixtures to result in 250 mg (16%) of a pale yellow oil.

Example 9

2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid

91.11 g (0.5 mol) of benzophenone and 45.92 g (0.85 mol) of sodiummethoxide were suspended in 150 ml of methyl tert-butyl ether (MTB) atroom temperature. After cooling to −10° C., 92.24 g (0.85 mol) of methylchloroacetate were added in such a way that the internal temperaturerose to 40° C. while continuing to cool in a bath at −10° C. The mixturewas then stirred without cooling at the autogenous temperature for onehour. After addition of 250 ml of water and brief stirring, the aqueousphase was separated off. The MTB phase was washed with 250 ml of dilutesodium chloride solution. After the solvent had been changed to methanol(250 ml), a solution of 1 g of p-toluenesulfonic acid in 10 ml ofmethanol was added at room temperature. The mixture was stirred atautogenous temperature for one hour and then heated to reflux. Whiledistilling out the methanol, 400 g of a 10% strength sodium hydroxidesolution was added dropwise, and finally 60 ml of water were added. Themethanol was distilled out until the bottom temperature reached 97° C.After cooling to 55° C., 190 ml of MTB were added and the mixture wasacidified to pH 2 with about 77 ml of concentrated HCl. After cooling toroom temperature, the aqueous phase was separated off and the organicphase was concentrated by distilling out 60 ml of MtB [sic]. The productwas crystallized by adding 500 ml of heptane and slowly cooling to roomtemperature. The coarsely crystalline solid was filtered off withsuction, washed with heptane and dried to constant weight in a vacuumoven at 40° C.

Yield: 108.9 g (80%), HPLC>99.5% area.

Example 10

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolutionwith L-proline methyl ester)

48.8 g of a 30% strength methanolic sodium methanolate solution (0.826mol) were added dropwise to 240 g of a 57% strength methanolic L-prolinemethyl ester hydrochloride solution (0.826 mol) at room temperature, and2.4 l of MTB and 225 g (0.826 mol) of2-hydroxy-3-methoxy-3,3-diphenylpropionic acid were added. After 2680 mlof MTB/methanol mixture had been distilled out with simultaneousdropwise addition of 2.4 l of MTB, the mixture was slowly cooled to roomtemperature, the crystals (R-2-hydroxy-3-methoxy-3,3-diphenylpropionicacid×L-proline methyl ester) were filtered off with suction, and thesolid was washed with 150 ml of MTB. The filtrate was concentrated bydistilling out 1.5 l of MTB, and 1.0 l of water was added. The pH wasadjusted to 1.2 with concentrated hydrochloric acid at room temperatureand, after stirring and phase separation, the aqueous phase wasseparated off and extracted with 0.4 l of MTB. The combined organicphases were extracted with 0.4 l of water. The residue after the MTB hadbeen stripped off was dissolved in 650 ml of toluene under reflux, andthe product was crystallized by seeding and slow cooling. Filtrationwith suction, washing with toluene and drying in a vacuum oven resultedin 78.7 g of S-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35%based on the racemate).

Chiral HPLC: 100% pure

HPLC: 99.8%

Example 11

S-2-Hydroxy-3-methoxy-3,3-diphenylpropionic acid (racemate resolutionwith (S)-1-(4-nitrophenyl)ethylamine)

30.5 g (0.184 mol) of (S)-1-(4-nitrophenyl)ethylamine were added to 100g (0.368 mol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid in 750ml of acetone and 750 ml of MTB under reflux, the mixture was seeded,boiled under reflux for one hour and slowly cooled to room temperaturefor crystallization. The crystals(S-2-hydroxy-3-methoxy-3,3-diphenylpropionicacid×(S)-1-(4-nitrophenyl)ethylamine) were filtered off with suction andwashed with MTB. The residue was suspended in 500 ml of water and 350 mlof MTB and then the pH was adjusted to 1.2 with concentratedhydrochloric acid at room temperature, and, after stirring and phaseseparation, the aqueous phase was separated off and extracted with 150ml of MTB. The combined organic phases were extracted with 100 ml ofwater. 370 ml of MTB were distilled out and then 390 ml of n-heptanewere added under reflux, and the mixture was slowly cooled to roomtemperature while the product crystallized. Filtration with suction,washing with n-heptane and drying in a vacuum oven resulted in 35.0 g ofS-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield 35% based on theracemate).

Chiral HPLC: 100% pure

HPLC: 99.8%

Example 12

Benzyl3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionate

24.48 g (90 mmol) of 3-methoxy-3,3-diphenyl-2-hydroxypropionic acid weredissolved in 150 ml of DMF, and 13.7 g (99 mmol) of potassium carbonatewere added. The suspension was stirred at room temperature for 30 min.Then 10.7 ml (90 mmol) of benzyl bromide were added dropwise over thecourse of 5 min, and the mixture was stirred for 1 h, during which thetemperature rose to 32° C.

To this mixture were successively added 24.84 g (180 mmol) of K₂CO₃ and20.52 g (90 mmol) of2-methanesulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentapyridine, and themixture was stirred at 80° C. for 3 h.

For workup, the contents of the flask were diluted with about 600 ml ofH₂O and cautiously acidified with concentrated HCl, and 250 ml of ethylacetate were added. 31.4 g of pure product precipitated and werefiltered off.

The ethyl acetate phase was separated from the mother liquor, theaqueous phase was extracted again with ethyl acetate, and the combinedorganic phases were concentrated. The oily residue (19 g) was purifiedby chromatography (cyclohexane/ethyl acetate=9/1) to result in a further10.5 g of pure product.

Total yield: 41.9 g (82.2 nmol){circumflex over (=)} 91%

Melting point 143-147° C.

MS: MH⁺=511

Example 13

3-Methoxy-2-(4-methoxy-(6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionic[sic] acid

40 g (78.4 mmol) of benzyl3-methoxy-2-(4-methoxy-6,7-dihydro-5H-cyclopentapyrimidin-2-yloxy)-3,3-diphenylpropionatewere dissolved in 400 ml of ethyl acetate/methanol (4:1), about 500 mgof palladium on active carbon (10%) were added, and the mixture wasexposed to a hydrogen atmosphere until no further gas was taken up. Thecatalyst was filtered off, the solution was evaporated, and the residuewas crystallized from ether.

Example 14

Ethyl 2S-3,3-diphenyloxirane-2-carboxylate

2.57 g (10.2 mmol) of ethyl 3,3-diphenylacrylate and 464 mg of4-phenylpyridine N-oxide were dissolved in 24 ml of methylene chloride,and 432 mg (6.5 mol %) of(5,5)-(+)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride were added. While cooling in ice, 6.4 ml of a 12%strength sodium hypochloride solution were added, and the mixture wasstirred while cooling in ice for 30 min and at room temperatureovernight. The solution was diluted to 200 ml with water, extracted withether, dried and evaporated. 2.85 g of a colorless oil were obtained.Purification by NPLC (cyclohexane:ethyl acetate=9:1) resulted in 1.12 gof oil with an enantiomer ratio of about 8:1 in favor of the Sconfiguration.

¹H-NMR [CDCl₃],

δ=1.0 (t, 3H); 3.9 (m, 3H); 7.3 (m, 10H)

Example 15

2-Methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol

46.9 g (330 mmol) of methyl cyclopentanone-2-carboxylate and 53.5 g (192mmol) of 5-methylisothiourea sulfate were successively added to 29.6 g(528 mmol) of KOH in 396 ml of methanol, and the mixture was stirred atroom temperature overnight, acidified with 1N hydrochloric acid anddiluted with water. The crystals which separated out were filtered offwith suction and dried. 20 g of crystals were obtained.

Example 16

sulfanyl 4-Chloro-2-methyl-6,7-dihydro-5H-cyclopentapyrimidine

255 ml of phosphorus oxychloride were added to 20 g (110 mmol), and themixture was stirred at 80° C. for 3 hours. Phosphorus oxychloride wasevaporated off, ice was added to the residue, and the crystals whichseparated out were filtered off with suction. 18.5 g of a brownish solidwere obtained.

Example 17

4-Methoxy-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine

18.05 g (90 mmol) of4-chloro-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine weredissolved in 200 ml of methanol. At 45° C., 16.7 g of sodium methoxide(as 30% strength solutions in methanol) were added dropwise, and themixture was stirred for 2 hours. The solution was evaporated, taken upin ethyl acetate and acidified with dilute hydrochloric acid, and theethyl acetate extract was evaporated. 15.5 g of an oil remained.

¹H-NMR [DMSO],

δ=2.1 (quintet, 2H); 2.5 (s, 3H); 2.8 (dt, 4H); 3.9 (s, 3H) ppm

Example 18

2-Methylsulfonyl-4-methoxy-6,7-dihydro-5H-cyclopentopyrimidine

15 g (76.2 mmol) of4-methoxy-2-methylsulfonyl-6,7-dihydro-5H-cyclopentapyrimidine weredissolved in 160 ml of glacial acetic acid/methylene chloride (1:1), and1.3 g of sodium tungstate were added. At 35° C., 17.5 ml (170 ml) of a30% strength H₂O₂ solution were added dropwise. The mixture was thendiluted with 500 ml of water and 100 ml of methylene chloride, and theorganic phase was separated off, dried and evaporated. 14 g of oilremained and were crystallized from ether.

¹H-NMR [CDCl₃],

δ=2.2 (quintet, 2H); 3.0 (dt., 4H); 3.3 (s, 3H); 4.1 (s, 3H) ppm

Example 19

1-Benzenesulfonyl-3-(4,6-dimethoxy-2-pyrimidinyloxy)-4-methoxy-4,4-diphenyl-2-butanone

0.37 g (2.4 mmol) of phenyl methane sulfone were dissolved in 10 ml ofdry THF and then, at −70° C., 2 eq. of butyllithium (2.94 ml; 1.6 molarsolution in hexane) were added dropwise. After 1 h at −70° C., 1 g (2.4mmol) of methyl2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropynoatedissolved in 5 ml of THF was added dropwise. The reaction mixture wasthen stirred at −70° C. for 1 h and at −10° C. for 1 h and then warmedto room temperature.

For workup, about 10 ml of saturated NH₄Cl solution were added dropwise,thorough extraction with ethyl acetate was carried out, and the combinedorganic phases with-saturated N—Cl solution and dried over Na₂SO₄. Theresidue obtained after drying and concentration was purified bychromatography on silica gel (n-heptane/ethyl acetate 15%→30%) andsubsequently MPLC on RP silica gel (acetonitrile/H₂O+TFA); 0.3 g of awhite amorphous powder was obtained as product.

Example 20

3,3-Diphenyloxiram-2-carbonitrile

3.1 g (54.9 mmol) of sodium methoxide were suspended in 20 ml of dry THFand then, at −10° C., a mixture of 5 g (27.4 mmol) of benzophenone and4.2 g (54.9 mmol) of chloroacetonitrile was added dropwise.

The reaction mixture was stirred at −10° C. for about 2 h, then pouredinto water and extracted several times with ethyl acetate. The combinedorganic phases were dried over Na₂SO₄ and concentrated, and the residuewas purified by chromatography on silica gel (n-heptane/ethyl acetate).

Yield: 1.2 g (20%)

¹H-NMR [CDCl₃],

δ=3.9 (s, 1H); 7.4-7.5 (m, 10H) ppm

Example 21

2-Hydroxy-3-methoxy-3,3-diphenylpropionitrile

6.5 (29.4 mmol) of 3,3-diphenyloxirane-2-carbonitrile were dissolved in60 ml of methanol and, at 0° C., about 2 ml of boron trifluorideetherate solution were added. The mixture was stirred further at 0° C.for 1 h and then at room temperature overnight. For workup it wasdiluted with diethyl ether and washed with saturated NaCl solution, andthe organic phase was dried over Na₂SO₄ and concentrated. The residuecomprised 7.3 g of a white amorphous powder which was used directly inthe subsequent reactions.

¹H-NMR [CDCl₃],

δ=2.95 (broad s, OH), 3.15 (s, 3H), 5.3 (s, 1H), 7.3-7.5 (m, 10) ppm

Example 22

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenylpropionitrile

7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile weredissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K₂CO₃ and 6.3 g (28mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. Themixture was stirred at room temperature for about 12 h, then poured intowater and extracted with ethyl acetate. The combined organic phases werewashed again with H₂O, dried and concentrated. The residue obtained inthis way was then purified by chromatography on silica gel(n-hepane/ethyl acetate).

Yield: 6.9 g of white amorphous powder

FAB-MS: 392 (M+H⁺)

¹H-NMR [CDCl₃],

δ=3.3 (s, 3H); 4.95 (s, 6H), 5.85 (S, 1H); 6.3 (s, 1H); 7.3-7.5 (m, 10H)ppm

Example 23

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1H-tetrazole

0.5 g (1.3 mmol) of nitrile was dissolved in 10 ml of toluene, and 85 mg(1.3 mmol) of NaN₃ and 460 mg (1.4 mmol) of Bu₃SnCl were successivelyadded, and then the mixture was refluxed for about 40 h. Cooling wasfollowed by dilution with ethyl acetate and washing with 10% aqueous KFsolution and with NaCl solution. After drying over MgSO₄ andconcentration there remained 1.0 g of a yellow oil, which was purifiedby chromatography on silica gel (n-heptane/ethyl acetate).

Concentration of the fractions resulted in 60 mg of the 1H-tetrazole and110 mg of the 1-methyltetrazole, each as amorphous white solids.

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1H-tetrazole

Electrospray-MS: 435 (M+H⁺)

¹H-NMR (CDCl₃):

δ (ppm) 3.28 (s, 3H), 3.85 (s, 6H), 5.75 (s, 1H), 7.25-7.40 (m, 10H),7.50 (s, 1H).

5-[2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methoxy-3,3-diphenyl)propyl]-1-methyltetrazole

Electrospray-MS; 471 (M+H⁺)

¹H-NMR (CDCl₃):

δ (ppm) 3.0 (s, 3H), 3.35 (s, 3H9 [sic], 3.80 (s, 6H), 5.75 (s, 1H),7.30-7.40 (m, 11H).

Example 24

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfinyl-3,3-diphenylpropionicacid

1.2 g (2.9 mmol) of2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionicacid were introduced into 15 ml of glacial acetic acid at 0° C. and 294μl of 30% strength H₂O₂ were added dropwise. The mixture was stirred atroom temperature overnight, poured into water, extracted with CH₂Cl₂ andwashed with sodium thiosulfate solution and brine. After drying, 1 g ofsubstance was isolated as a white foam.

Example 25

2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionicacid

0.6 g (1.45 mmol) of2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methylsulfonyl-3,3-diphenylpropionicacid was introduced into 15 ml of glacial acetic acid at roomtemperature, and 294 μl of 30% strength H₂O₂ were added dropwise. Themixture was stirred at room temperature overnight, heated at 50° C. fora further 3 h, poured into water and washed with sodium thiosulfatesolution and brine. After drying, 400 mg were isolated as a white solid.

The compounds listed in Table 1 can be prepared in a similar way.

TABLE I

No. R¹ R⁴, R⁵ R⁶ R² R³ X Y Z m.p.[° C.] I-1 OMe Phenyl Methyl OMe OMe CHO O 81 I-2 OH Phenyl Methyl OMe OMe CH O O 167 I-3 OH PhenylCH₂—CH₂—S—CH₃ OMe OMe CH O O I-4 OH Phenyl Ethyl OMe OMe CH O O81(decomp.) I-5 OH Phenyl iso-Propyl OMe OMe CH O O 182 I-6 OH PhenylMethyl OMe OMe CH O S 168 I-7 OH Phenyl CH₂—CH₂—SO₂—CH(CH₃)₂ OMe OMe CHO O I-8 OH Phenyl CH₂—CH₂—SO₂—CH(CH₃)₂ OMe OMe CH S O I-9 OH PhenylCH₂—CH₂—SO₂—CH(CH₃)₂ OMe OMe C—CH(CH₃)₂ O O I-10 OH PhenylCH₂—CH₂—SO₂—CH(CH₃)₂ OMe OMe C—CH(CH₃)₂ O O I-11 OH PhenylCH₂—CH₂—SO₂—CH(CH₃)₂ OMe NH—OCH₃ CH O O I-12 OH Phenyl n-Propyl OMe OMeCH O O 174 I-13 OMe Phenyl n-Propyl OMe OMe CH O O I-14 OH Phenyln-Propyl OEt OEt CH O O I-15 OH Phenyl iso-Butyl OMe OMe CH O O I-16 OHPhenyl iso-Butyl OMe OMe CH O O I-17 OH Phenyl iso-butyl OMe O—CH₂—CH₂—CO O I-18 OH Phenyl tert-Butyl OMe OMe CH O O I-19 OH Phenyl CyclopropylOMe OMe CH O O I-20 OH Phenyl Cyclopentyl OMe OMe CH O O I-21 OH PhenylCyclohexyl OMe OMe CH O O I-22 OH Phenyl (CH₃)₃C—CH₂—CH₂ OEt OEt CH O OI-23 OH Phenyl (CH₃)₂CH—CH₂—CH₂—CH₂ OMe OMe CH O O 173 I-24 OH PhenylHO—CH₂—CH₂ OMe OMe CH O O I-25 OH Phenyl HO₂C—(CH₂)₂— OMe OMe CH O OI-26 OH Phenyl Cyclopropylmethylene [sic] OMe OMe CH O O 115 I-27 OHPhenyl H OMe OMe CH O O I-28 OH Phenyl Methyl OMe OMe CH O — I-29 OHPhenyl Phenyl OMe OMe CH O O 136 I-30 OH Phenyl Phenyl OMeO—CH(CH₃)—CH₂—C O O I-31 OMe Phenyl Phenyl OMe OMe CH O O I-32 OH Phenyl4-Isopropyl-Phenyl OMe OMe CH O O I-33 OH Phenyl 4-Me—S-Phenyl OMe OMeCH O O I-34 OH Phenyl 4-Me—O-Phenyl OMe OMe CH O O I-35 OH Phenyl3-Et-Phenyl OMe OMe CH O O I-36 OH Phenyl 2-Me-Phenyl OMe OMe CH O OI-37 OH Phenyl 2-Cl-Phenyl OMe OMe CH O O I-38 OH Phenyl 3-Br-Phenyl OMeOMe CH O O I-39 OH Phenyl 4-F-Phenyl OMe OMe CH O O I-40 OH Phenyl4-F-Phenyl OMe OMe CH S O I-41 OH Phenyl 4-CH₃-Phenyl OMe OMe CH O OI-42 OH Phenyl 3-NO₂-Phenyl OMe OMe CH O O I-43 OH Phenyl 2-HO-PhenylOMe OMe CH O O I-44 OH Phenyl 3,4-Dimethoxyphenyl OMe OMe CH O O I-45 OHPhenyl 3,4-Dioxomethylenephenyl [sic] OMe OMe CH O O I-46 OH Phenyl3,4,5-Trimethoxyphenyl OMe OMe CH O O I-47 OH Phenyl Benzyl OMe OMe CH OO I-48 OH Phenyl 2-Cl-Benzyl OMe OMe CH O O I-49 OH Phenyl 3-Br-BenzylOMe OMe CH O O I-50 OH Phenyl 4-F-Benzyl OMe OMe CH O O I-51 OH Phenyl2-Me-Benzyl OMe OMe CH O O I-52 OH Phenyl 2-Me-Benzyl OMe O—CH═CH—C O OI-53 OH Phenyl 3-Et-Benzyl OMe OMe CH O O I-54 OH Phenyl4-iso-Propyl-Benzyl OMe OMe CH O O I-55 OH Phenyl 4-NO₂-Propyl-BenzylOMe OMe CH O O I-56 OH Phenyl 2-Me-5-Propyl-Benzyl OMe OMe CH O O I-57OH Phenyl 2-Me-5-Propyl-Benzyl OEt OEt CH O O I-58 OH Phenyl4-Me-2-Propyl-Benzyl OMe OMe CH O O I-59 OH Phenyl3,4-Dioxomethylenebenzyl [sic] OMe OMe CH O O I-60 OH 4-F-Phenyl MethylOMe OMe CH O O 163-165(decomp.) I-61 OMe 4-F-Phenyl Methyl OEt OEt CH OO I-62 OH 4-Cl-Phenyl Methyl OMe OMe CH O O I-63 OH 4-Me—O-Phenyl MethylOMe OMe CH O O I-64 OH 4-Me—O-Phenyl Ethyl OMe OMe CH O O I-65 OH4-Me-Phenyl Methyl OMe OMe CH O O I-66 OH 4-Me-Phenyl Methyl OMeO—CH₂—CH₂—C O O I-67 OH 3-CF₃-Phenyl n-Propyl OMe OMe CH O O I-68 OH3-CF₃-Phenyl n-Propyl OMe O—CH(CH₃)—CH₂—C O O I-69 OH 4-NO₂-PhenylMethyl OMe OMe CH O O I-70 OH 4-NO₂-Phenyl Methyl OMe O—CH═CH—C O O I-71OH 3-Cl-Phenyl Ethyl OMe OMe CH O O I-72 OH 2-F-Phenyl Methyl OMe OMe CHO O 193-194(decomp.) I-73 OH 2-F-Phenyl Methyl OMe OMe CH S O I-74 OH2-Me—O-Phenyl Methyl OMe OMe CH O O I-75 OH 2-Me—O-Phenyl Methyl OMe OMeCH O S I-76 OH 3,4-Dimethoxyphenyl Methyl OMe OMe CH O O I-77 OH3,4-Dioxomethylenephenyl [sic] Methyl OMe OMe CH O O I-78 OHp-CF₃-Phenyl Methyl OMe OMe CH O O I-79 OH Phenyl Methyl OMe OEt CH O OI-80 OMe Phenyl Methyl OMe OEt CH S O I-81 OH Phenyl Ethyl OMe NH—OMe CHO O I-82 OH p-Me—O-Phenyl n-Propyl OMe OCF₃ CH O O I-83 OH Phenyl MethylOMe CF₃ CH O O I-84 OH Phenyl Methyl OMe CF₃ N O O I-85 OH3,4-Dimethoxyphenyl Benzyl Me Me O O I-86 OH 3,4-Dimethoxyphenyl MethylOMe O—CH₂—CH₂—C O O I-87 OH Phenyl Methyl OMe O—CH₂—CH₂—C O O126(decomp.) I-88 OH Phenyl Methyl OMe O—CH(CH₃)—CH₂—C O O I-89 OHPhenyl Methyl OMe N(CH₃)—CH═CH—C O O 118 I-90 OH Phenyl Methyl OMeS—C(CH₃)═C(CH₃C O O I-91 OH Phenyl Methyl OMe O—C(CH₃)═CH—C O O I-92 OHPhenyl Methyl Me O—C(CH₃)═CH—C O O I-93 OH Phenyl Methyl Me O—CH═CH—C OO I-94 OH 4-F-phenyl Methyl Me S—CH═CH—C O O I-95 OH 4-F-phenyl H OMeOMe CH O O I-96 OH Phenyl Methyl OMe CH₂—CH₂—CH₂—C O O 149-151(decomp.)I-97 OH Phenyl Methyl Methyl CH₂—CH₂—CH₂—C O O 157(decomp.) I-98 OHPhenyl Methyl Ethyl CH₂—CH₂—CH₂—CH₂—C O O I-99 OH Phenyl Methyl OMeCH₂—CH₂—CH₂—CH₂—C O O I-100 OH Phenyl Methyl Me Me CH O O I-101 OHPhenyl Methyl Et Et CH O O I-102 OH Phenyl Methyl Me Me C—CH₃ O O I-103OH Phenyl Methyl OMe Me CH O O I-104 OH Cyclohexyl Methyl OMe OMe CH O OI-105 OH Cyclohexyl Methyl OMe CH₂—CH₂—CH₂—C O O I-106 OH Phenyl MethylOCH₃ OCH₃ CH S S I-107 OH Phenyl Methyl OCH₃ OCH₃ CH O S 134 I-108 OCH₃Phenyl Methyl OCH₃ OCH₃ CH S S I-109 OH Phenyl Methyl OCH₃ OCH₃ CH O OI-110 OCH₃ 2-Fluorophenyl Methyl OCH₃ OCH₃ CH O O I-111 OC₂H₅3-Chlorophenyl Methyl OCH₃ OCH₃ N O O I-112 ON(CH₃)₂ 4-BromophenylMethyl CF₃ CF₃ CH S O I-113 O—CH₂—C═CH Phenyl Ethyl OCH₃ CF₃ CH O OI-114 OH Phenyl Propyl OCH₃ OCF₃ CH O S I-115 OCH₃ Phenyl i-Propyl OCH₃CH₃ CH O O I-116 OC₂H₅ Phenyl s-Butyl OCH₃ Cl CH S O I-117 ON(CH₃)₂2-Methylphenyl Methyl OCH₃ OCH₃ CH O O I-118 ON(CH₃)₂ 3-MethoxyphenylMethyl OCH₃ OCH₃ CH O O I-119 ON═C(CH₃)₂ 4-Nitrophenyl Methyl OCH₃ OCH₃CH O O I-120 ON(CH₃)₂ Phenyl 1-Phenylpropyn-3-yl OCH₃ OCF₃ N O S I-121ON═C(CH₃)₂ 2-Hydroxyphenyl Methyl OCH₃ CH₃ N O O I-122 ONSO₂C₆H₅3-Trifluoromethylphenyl Methyl OCH₃ Cl N O O I-123 NHPhenyl4-Dimethylaminophenyl Methyl OCH₃ OCH₃ CH S O I-124 OC₂H₅ PhenylTrifluoroethyl CH₃ CH₃ CH O O I-125 ON(CH₃)₂ Phenyl Benzyl Cl Cl CH O OI-126 ON(CH₃)₂ Phenyl 2-Methoxyethyl OCH₃ —O—CH₂—CH₂— S O I-127 OHPhenyl Phenyl OCH₃ OCH₃ CH O O I-128 OH Phenyl Phenyl OCH₃ —O—CH₂—CH₂— OO I-129 OH Phenyl Phenyl OCH₃ OCH₃ N O O I-130 OH Phenyl Phenyl OCH₃OCH₃ CH S O I-131 OH Phenyl Phenyl OCH₃ OCH₃ CH S S I-132 OH PhenylPhenyl OCH₃ OCH₃ CH O S I-133 OH Phenyl Phenyl OCH₃ OCH₃ CH O O I-134 OHPhenyl Phenyl OCH₃ OCH₃ CH O O I-135 OH —(CH₂)₅— Phenyl Phenyl OCH₃ CH OO I-136 OH Phenyl 2-Thiazolyl OCH₃ OCH₃ CH O O I-137 OCH₃ 2-FluorophenylPhenyl OCH₃ OCH₃ CH O O I-138 OC₂H₅ 3-Chlorophenyl Phenyl OCH₃ OCH₃ N OO I-139 ON(CH₃)₂ 4-Bromophenyl Phenyl CF₃ CF₃ CH O O I-140 O—CH₂≡CHPhenyl 2-Fluorophenyl OCH₃ CF₃ CH O O I-141 OH Phenyl 3-ChlorophenylOCH₃ OCF₃ CH O S I-142 OCH₃ Phenyl 4-Bromophenyl OCH₃ CH₃ CH O O I-143OC₂H₅ Phenyl 4-Thiazolyl OCH₃ Cl CH S O I-144 ON(CH₃)₂ 2-MethylphenylPhenyl OCH₃ OCH₃ CH O O I-145 ON═C(CH₃)₂ 3-Methoxyphenyl Phenyl OCH₃OCH₃ CH O O I-146 OH Phenyl Methyl OCH₃ —CH₂—CH₂—CH₂—C O O I-147 OH4-Fluorophenyl Methyl OCH₃ OCH₃ CH O O 168(decomp.) I-148 OH4-Fluorophenyl Methyl OCH₃ —CH₂—CH₂—CH₂—C O O I-149 NH—SO—C₆H₅4-Nitrophenyl Phenyl OCH₃ OCH₃ CH O O I-150 OCH₃ Phenyl 3-ImidazolylOCH₃ —O—CH₂—CH₂ O O I-151 OC₂H₅ Phenyl 4-Imidazolyl OCH₃ CF₃ N S O I-152ON(CH₃)₂ Phenyl 2-Pyrazolyl OCH₃ OCF₃ N O S I-153 ON═C(CH₃)₂2-Hydroxyphenyl Phenyl OCH₃ CH₃ N O O I-154 NH—SO₂—C₆H₅3-Trifluoromethylphenyl Phenyl OCH₃ Cl N O O I-155 NHPhenyl4-Dimethylaminophenyl Phenyl OCH₃ OCH₃ CH S O I-156 ONa Phenyl PhenylOCH₃ OCH₃ CH S S I-157 O—CH₂—C≡C Phenyl Phenyl OCH₃ OCH₃ N S S I-158 OHPhenyl Phenyl CF₃ CF₃ CH O S I-159 OCH₃ Phenyl Phenyl OCF₃ OCF₃ CH O OI-160 OC₂H₅ Phenyl 2-Dimethylaminophenyl CH₃ CH₃ CH O O I-161 ON(CH₃)₂Phenyl 3-Hydroxyphenyl Cl Cl CH O O I-162 ON═C(CH₃)₂ Phenyl4-Trifluoromethylphenyl OCH₃ —O—CH₂—CH₂— S O I-163 NH—SO₂—C₆H₅ Phenyl2-Oxazolyl OCH₃ CF₃ N S S I-164 OH Phenyl Methyl CH₃ CH₃ CH O O I-165 OHCyclohexyl Methyl OCH₃ OCH₃ CH O O I-166 OH Cyclohexyl Methyl OCH₃CH₂—CH₂—CH—C O O I-167 OH Phenyl Methyl N N(CH₃)₂ CH O O (CH₃)₂ I-168 OHPhenyl Methyl OCH₃ OCH₃ CH O SO₂ I-169 OH Phenyl Methyl OCH₃ OCH₃ CH OSO₂ I-170 OH 3-F-Phenyl Me OMe OMe CH O O I-171 OH 3-F-Phenyl Me OMeCH₂—CH₂—CH₂—C O O I-172 OH 4-F-Phenyl Me OMe CH₂—CH₂—CH₂—C O O 142-143191° C. I-173 OH 3-MeO-Phenyl Me OMe CH₂—CH₂—CH₂—C O O 158-161(decomp.)I-174 OH 3-MeO-Phenyl Me OMe OMe CH O O I-175 OH 3-MeO-Phenyl Et OMeCH₂—CH₂—CH₂—C O O I-176 OH Phenyl HO—CH₂—CH₂ OMe CH₂—CH₂—CH₂—C O O I-177OH Phenyl Me NMe₂ NMe₂ N O O 181 I-178 OH Phenyl Me OMe OMe N O O I-180NH—SO₂—Phenyl Phenyl Me OMe OMe CH O O I-181 NH—SO₂—Me Phenyl Me OMe OMeCH O O I-182 CH₂—SO₂-Phenyl Phenyl Me OMe OMe CH O O I-183 CH₂—SO₂-MePhenyl Me OMe OMe CH O O I-184 —CN Phenyl Me OMe OMe CH O O I-185Tetrazole [sic] Phenyl Me OMe OMe CH O O I-186 NH—SO₂-Phenyl Phenyl MeOMe OMe CH O O 167 I-187 N-Methyltetrazole Phenyl Me OMe OMe CH O O[sic] I-188 ONa Phenyl Me OMe —O—CH₂—CH₂—C— O O 122-139(zers.) I-189 OHo-F-Phenyl Me OMe —O—CH₂—CH₂—C— O O 140-144(decomp.) I-190 OHm-Me-Phenyl Me OMe OMe CH O O 169-177 I-191 OH m-Me-Phenyl Me OMe—O—CH₂—CH₂—C— O O 119-135(decomp.) I-192 OH p-F-Phenyl Me OMe Me CH O O137-140(decomp.) I-193 OH m-F-Phenyl Me Me —O—CH₂—CH₂—C— O O 150-152I-194 OH p-F-Phenyl Me Me —O—CH₂—CH₂—C— O O 169-170

TABLE II

No. R¹ A R⁶ R² R³ X Y Z m.p. (° C.) II-1 OH Bond Methyl OMe OMe CH O O96-98 II-2 OH CH₂ Methyl OMe OMe CH O O II-3 OH CH₂—CH₂ Methyl OMe OMeCH O O II-4 OH CH═CH Methyl OMe OMe CH O O II-5 OH O Methyl OMe OMe CH OO II-6 OH S Methyl OMe OMe CH O O II-7 OH NH(CH₃) Methyl OMe OMe CH O OII-8 OH Bond Isopropyl OMe OMe CH O O 137-139 II-9 OH Bondp-Isopropylphenyl OMe OMe CH O O II-10 OH Bond Benzyl OMe OMe CH O OII-11 OH CH═CH Ethyl OMe OMe CH O O II-12 OH CH═CH (CH₃)₂—CH₂—CH₂ OMeOMe CH O O II-13 OH CH═CH Cyclopropylmethylene [sic] OMe OMe CH O OII-14 OH CH═CH Methyl OMe O—CH₂—CH₂—C O O II-15 OH CH₂—CH₂ Ethyl OMeO—CH═CH—C O O II-16 OH CH₂═CH₂ Methyl OMe CH₂—CH₂—CH₂—C O O II-17 OHBond Methyl OMe CH₂—CH₂—CH₂—C O O 147

EXAMPLE 35

Receptor binding data were measured by the binding assay described abovefor the compounds listed below.

The results are shown in Table 2 [sic].

TABLE 2 [sic] Receptor binding data (K_(i) values) Compound ET_(A) [nM]ET_(B) [nM] I-2 6 34 I-29 86 180 I-5 12 160 I-4 7 2500 I-87 1 57 I.89 869300 I-103 0.4 29 I-107 3 485 I-12 19 1700 I-26 23 2000 I-23 209 1100I-47 150 1500 I-60 33 970 I-96 0.6 56 II-3 107 7300 II-1 28 2300

We claim:
 1. A compound of the formula I

where R is formyl, tetrazole, nitrile, a COOH group or a radical whichcan be hydrolyzed to COOH, and the other substituents have the followingmeanings: R² hydrogen, hydroxyl, NH₂, NH(C₁-C₄-alkyl), N(C₁-C₄-alkyl)₂,halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio; X CR¹⁴ which forms together with CR³ a 5-membered ringwhich can be substituted by one or two C₁-C₄-alkyl groups; R³ is linkedto CR¹⁴ as indicated above to give a 5-membered ring; R⁴ and R⁵, whichcan be identical or different, are phenyl or naphthyl, which can besubstituted by one or more of the following radicals: halogen, nitro,cyano, hydroxyl, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, phenoxy, C₁-C₄-alkylthio, amino, C₁-C₄-alkylamino, orC₁-C₄-dialkylamino; or phenyl or naphthyl, which are connected togetherin the ortho position via a direct linkage, a methylene, ethylene orethenylene group, an oxygen or sulfur atom or an SO₂, NH or N-alkylgroup; or C₃-C₇-cycloalkyl; R⁶ hydrogen, C₁-C₈-alkyl, C₃-C₆-alkenyl,C₃-C₆-alkynyl or C₃-C₈-cycloalkyl, where each of these radicals can besubstituted one or more times by: halogen, nitro, cyano, C₁-C₄-alkoxy,C₃-C₆-alkenyloxy, C₃-C₆-alkynyloxy, C₁-C₄-alkylthio, C₁-C₄-haloalkoxy,C₁-C₄-alkylcarbonyl, C₁-C₄-alkoxycarbonyl, C₃-C₈-alkylcarbonylalkyl,C₁-C₄-alkylamino, di-C₁-C₄-alkylamino, phenyl or phenoxy which issubstituted one or more times by halogen, nitro, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio;phenyl or naphthyl, each of which can be substituted by one or more ofthe following radicals: halogen, nitro, cyano, hydroxyl, amino,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, phenoxy,C₁-C₄-alkylthio, C₁-C₄-alkylamino, C₁-C₄-dialkylamino or dioxomethyleneor dioxoethylene; a five or six-membered heteroaromatic moietycontaining one to three nitrogen atoms and/or one sulfur or oxygen atom,which can carry one to four halogen atoms and/or one or two of thefollowing radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy, C₁-C₄-alkylthio, phenyl, phenoxy or phenylcarbonyl, itbeing possible for the phenyl radicals in turn to carry one to fivehalogen atoms and/or one to three of the following radicals:C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/orC₁-C₄-alkylthio; Y sulfur or oxygen or a single bond; Z sulfur, oxygen,—SO— or —SO₂—.
 2. The compound of the formula I as defined in claim 1,wherein R¹⁴ together with R³ is a radical selected from the groupconsisting of —CH₂—CH₂—CH₂— and —CH═CH—CH₂—.
 3. The compound of theformula I as defined in claim 1, wherein R is CO₂H.
 4. The compound ofthe formula I as defined in claim 1, wherein R² is methoxy.
 5. Thecompound of the formula I as defined in claim 1, wherein R⁴ and R⁵ eachare phenyl.
 6. The compound of the formula I as defined in claim 1,wherein R⁶ is C₁-C₈-alkyl.
 7. The compound of the formula I as definedin claim 1, wherein Y is oxygen.
 8. The compound of the formula I asdefined in claim 1, wherein Z is oxygen or sulfur.
 9. The compound ofthe formula I as defined in claim 1, wherein Z is oxygen.
 10. Thecompound of the formula I as defined in claim 1, wherein R is tetrazole,nitrile or a group

where R¹ has the following meanings: a) hydrogen; b) succinylimidoxy; c)a five-membered heteroaromatic ring linked by a nitrogen atom, selectedfrom the group consisting of: pyrrolyl, pyrazolyl, imidazolyl andtriazolyl, which ring can carry one or two halogen atoms and or one ortwo of the following radicals: C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₄-alkylthio; d) a radical

where m is 0 or 1 and R⁷ and R⁸, which can be identical or different,have the following meanings: hydrogen, C₁-C₈-alkyl, C₃-C₆-alkenyl,C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, where these alkyl, cycloalkyl, alkenyland alkynyl groups can each carry one to five halogen atoms and/or oneor two of the following groups: C₁-C₄-alkyl, C₁-C₄-alkoxy,C₁-C₄-alkylthio, C₁-C₄-haloalkoxy, C₃-C₆-alkenyloxy, C₃-C₆-alkenylthio,C₃-C₆-alkynyloxy or C₃-C₆alkynylthio, C₁-C₄-alkylcarbonyl,C₁-C₄-alkoxycarbonyl, C₃-C₅-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl,C₃-C₆-alkenyloxycarbonyl or C₃-C₆-alkynyloxycarbonyl, phenyl, which canbe substituted one or more times by halogen, nitro, cyano,C₃-C₆-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio,di-C₁-C₄-alkylamino, or R⁷ and R⁶ together form a C₄-C₇-alkylene chainwhich can be substituted by C₁-C₄-alkyl, and may contain a hetero atomselected from the group consisting of oxygen, sulfur and nitrogen, or R⁷and R⁸ together form a CH₂—CH═CH—CH₂ or CH═CH—(CH₂)₃ chain; e) a radical

where k is 0, 1 and 2, p is 1, 2, 3 and 4, and R⁹ is C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl or phenyl, which can besubstituted one or more times by halogen, nitro, cyano,C₃-C₆-alkenylcarbonyl, C₃-C₆-alkynylcarbonyl, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or C₁-C₄-alkylthio; f) aradical OR¹⁰, where R¹⁰ is hydrogen, the cation of an alkali metal or analkaline earth metal or an environmentally compatible organic ammoniumion; C₃-C₈-cycloalkyl which may carry one to three C₁-C₄-alkyl groups;C₁-C₈-alkyl which may carry one to five halogen atoms and/or one of thefollowing radicals: C₁-C₄-alkoxy, C₁-C₄-alkylthio, cyano,C₁-C₄-alkylcarbonyl, C₃-C₈-cycloalkyl, C₁-C₄-alkoxycarbonyl, phenyl,phenoxy or phenylcarbonyl, where the aromatic radicals in turn may carryone to five halogen atoms and/or one to three of the following radicals:nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy,C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio; C₁-C₈-alkyl which may carry oneto five halogen atoms and which carries one of the following radicals: a5-membered heteroaromatic ring containing one to three nitrogen atoms ora nitrogen atom and an oxygen or sulfur atom, which may carry one tofour halogen atoms and/or one or two of the following radicals: nitro,cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl,C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio; C₂-C₆-alkyl which carries oneof the following radicals in position 2: C₁-C₄-alkoxyimino,C₃-C₆-alkynyloxyimino, C₃-C₆-haloalkenyloxyimino or benzyloxyimino;C₃-C₆-alkenyl or C₃-C₆-alkynyl which may carry one to five halogenatoms; phenyl which may carry one to five halogen atoms and/or one tothree of the following radicals: nitro, cyano, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and/or C₁-C₄-alkylthio;a 5-membered heteroaromatic ring which is bonded via a nitrogen atom andcontaining one to three nitrogen atoms, which may carry one or twohalogen atoms and or one or two of the following radicals: C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, phenyl, C₁-C₄-haloalkoxy and/orC₁-C₄-alkylthio; a radical

where R¹¹ and R¹², which may be identical or different are: C₁-C₈-alkyl,C₃-C₆-alkenyl, C₃-C₆-alkynyl, C₃-C₈-cycloalkyl, it being possible forthese radicals to carry a C₁-C₄-alkoxy, C₁-C₄-alkylthio and/or phenylwhich may carry one to five halogen atoms and/or one to three of thefollowing radicals: nitro, cyano, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy, CL-C₄-haloalkoxy and/or C₁-C₄-alkylthio; phenyl which maycarry one or more of the following radicals: halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio; or R¹¹ and R¹² together form a C₃-C₁₂-alkylene chainwhich may carry one to three C₁-C₄-alkyl groups and which may contain ahetero atom selected from the group consisting of nitrogen, oxygen andsulfur; g) a radical

where R¹³ is C₁-C₄-alkyl, C₃-C₆-alkenyl, C₃-C₆-alkynyl,C₃-C₈-cycloalkyl, it being possible for these radicals to carry aC₁-C₄-alkoxy, C₁-C₄-alkylthio and/or a phenyl radical, or phenyl whichmay carry one or more of the following radicals: halogen, nitro, cyano,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy orC₁-C₄-alkylthio.